Plasma Drug Concentration-time Profile Research Articles

A Technique to Estimate In Vivo Dissolution Profiles Without Data from a Solution

Dissolution tests are expected to ensure adequate in vivo product performance. Given the recent progress in the ability to predict of human permeability, it is possible to synthesize the plasma drug concentration-time profile from human permeability predictions and the results of the first-in-human trial and use these data to synthesize a pharmacokinetic profile for a solution and provide an initial estimate of the in vivo dissolution profile. This manuscript provides details of such a deconvolution methodology in order to provide an initial estimate of in vivo dissolution. Plasma metoprolol concentration-time data from a previously published study examining the pharmacokinetics of three metoprolol formulations (100 mg), slow, moderate, and fast releasing, and an oral solution (50 mg) were used to estimate in vitro dissolution profiles. A one-compartment unit impulse function was used, and the absorption rate was estimated from animal permeability data (synthetic solution method). The results were compared to those obtained using a unit impulse function estimated from the oral solution data. In vivo dissolution profiles estimated from animal permeability data were similar to those estimated from the oral solution data. Ratios of absorption rate constants (synthetic solution method/oral solution) ranged from 1 to 1.3. The synthetic solution method offers a way to estimate in vivo dissolution profile through deconvolution. It is applicable in cases where it is not possible or feasible to obtain data from a solution. It performs best in cases where dissolution is the rate-limiting step in the absorption process.

The Corrected Traditional Equations for Calculation of Hepatic Clearance that Account for the Difference in Drug Ionization in Extracellular and Intracellular Tissue Water and the Corresponding Corrected PBPK Equation

The estimation of hepatic clearance, Clh, using in vitro data on metabolic stability of compound, its protein binding and blood–plasma equilibrium concentration ratio is commonly performed using well-stirred, parallel tube or dispersion models. It appears that for ionizable drugs there is a difference of the steady-state concentrations in extracelluar and intracellular water (at hepatocytes), where metabolism takes place. This occurs due to the different pH of extra- and intracellular water (7.4 and 7.0, respectively). The account of this fact leads to the novel equations for Clh . These equations include the additional parameter named ionization factor, FI, which is the ratio of the unionized drug fractions in plasma and intracellular tissue water (or the ratio of the unbound drug concentrations in intracellular tissue water and plasma at equilibrium). For neutral drugs FI = 1 and the novel equations coincide with the traditional ones. It is shown that the account of this factor may yield the calculated Clh up to 6.3-fold greater than that obtained by the traditional equations for the strong diprotic basic compounds, and up to 6.3-fold smaller for the strong diprotic acidic compounds. For triprotic acids and bases the difference could be as much as 15-fold. The account of pH difference between extra- and intracellular water also results in the change of the term commonly used to describe drug metabolic elimination rate in physiologically based pharmacokinetic (PBPK) equation. This consequently may lead to a noticeable change of drug concentration-time profiles in plasma and tissues. The effect of ionization factor is especially pronounced for the low-extraction ratio drugs. The examples of significant improvement in the prediction of hepatic clearance due to the account of ionization factor are provided. A more general equation for hepatic clearance, which accounts for ionization factor and possible drug uptake and efflux, is obtained.

Pharmacokinetic interaction between efavirenz and rifampicin in healthy volunteers

Rifampicin induces the metabolism of efavirenz in humans. This study evaluated efavirenz bioavailability after rifampicin administration to healthy volunteers. A 3-week, before-and-after trial was performed on 8 healthy volunteers. The pharmacokinetic parameters were: plasma drug concentration-time profile from 0 to 72 h (AUC0-72), plasma drug concentration-time profile from 0 h to infinity (AUC0-inf), maximal drug concentration (Cmax), time to reach maximal drug concentration (tmax), and time to reach half the initial drug concentration in elimination phase (t1/2). After an overnight fast, the volunteers ingested one efavirenz 600 mg tablet, then blood samples were drawn to evaluate plasma efavirenz levels at 0, 2, 3, 4, 5, 6, 24, 72, 120, and 168 h. The procedure was repeated after a 1-week induction period of 450 mg/day. Paired-t test and Wilcoxon matched-pairs test were used for differences between mean concentrations. Baseline mean AUC0-72 was 46.80 ± 9.27 µg/ml.h, AUC0-inf was 96.38 ± 38.10 µg/ml.h, Cmax 2.19 ± 0.68 µg/ml.h, tmax 4.50 ± 0.93 h, and t1/2 96.60 ± 42.38 h. Post-induction values were significantly increased: AUC0-72 9.53 ± 11.26 µg/ml.h (p < 0.05; CI95% = 0.112 - 18.940), AUC0-inf 37.24 ± 42.43 (p < 0.05; CI95% = 0.021 - 0.406) µg/ml.h, and tmax 1.13 ± 0.99 h (p < 0.05; CI95% = 0.296 - 1.953). No significant reduction occurred in post-rifampicin induction means of Cmax and t1/2. Co-administration of a single dose of efavirenz 600 mg/day with 1-week rifampicin 450 mg/day significantly reduced efavirenz bioavailability in healthy volunteers.

Pharmacokinetics and Tissue Distribution of Dual-Targeting Daunorubicin Liposomes in Mice

Background: To circumvent the problem of transporting anticancer drugs across the blood-brain barrier (BBB) to target brain tumors, we have previously developed dual-targeting daunorubicin liposomes modified with 4-aminophenyl-α-D-manno-pyranoside and transferrin molecules. The objective of the present study was to evaluate the pharmacokinetics and distribution of daunorubicin after intravenous administration of dual-targeting daunorubicin liposomes. Methods: We evaluated pharmacological parameters in normal KunMing mice. Drug concentrations in plasma, heart, spleen, lung, kidney and brain were measured using HPLC-UV. Results: The plasma drug concentration-time profile of the daunorubicin dual-targeting liposomes decreased more slowly than free daunorubicin in the initial phase and maintained higher drug levels in the terminal phase, resulting in longer blood exposure to daunorubicin liposomes compared with the free drug. Daunorubicin levels were lower in heart tissue and significantly higher in brain tissue after administration of the dual-targeting liposomes compared with the free drug. Daunorubicin was detected at varying levels in the liver, spleen, lung and kidney tissues. Conclusion: Our results indicate that dual-targeting daunorubicin liposomes improve the daunorubicin blood circulation time and show an enhanced drug transport potential across the BBB.

Formulation Variation and in Vitro-in Vivo Correlation for a Rapidly Swellable Three-Layered Tablet of Tamsulosin HCl

In order to develop a preferable once-a-day oral tablet formulation, various formulations of three-layered tablets containing tamsulosin HCl as a hydrophilic model drug were evaluated and compared with a commercial reference, tamsulosin OCAS®. When the test tablet was exposed to a release medium, the medium quickly permeated to the mid-layer and the two barrier layers swelled surrounding the mid-layer rapidly. Volume expansion showed faster and enough swelling of the three-layered tablet up to 2 h. Larger amount of barrier layers caused reduced release kinetics and a high molecular weight polymer showed more resistance against agitation force. A formulation with water-soluble mid-layer showed fast erosion decreasing its volume significantly. On the pharmacokinetic study, the mean ratio of area under the curve (AUC) and C(max) for the test formulation to the reference was 0.69 and 0.84, respectively, showing that the absorption of the drug was less complete than the reference. Plasma concentration at 24 h of the test formulation was higher than the reference. The Wagner-Nelson method showed that decreased initial dissolution rate might be the cause of the less complete absorption. On considering in vitro-in vivo correlation (IVIVC), level A, the reference (R²=0.981) showed more linear relationship than the test (R²=0.918) due to the decreased dissolution and absorption rate of the formulation. This result suggests that the in vitro dissolution profiles and release kinetics might be useful in correlating absorption kinetics as well as overall plasma drug concentration-time profiles for formulation studies.

Variability and Impact on Design of Bioequivalence Studies

In 2008, the European Agency for the Evaluation of Medicinal Products released a draft guidance on the investigation of bioequivalence for immediate release dosage forms with systemic action to replace the former guidance of a decade ago. Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75-133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003-2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe.

Seasonal Influence on Insulin and Cortisol Results from Overnight Dexamethasone Suppression Tests (DST) in Normal and Previously Laminitic Ponies

Seasonal Influence on Insulin and Cortisol Results from Overnight Dexamethasone Suppression Tests (DST) in Normal and Previously Laminitic Ponies

A single‐dose pharmacokinetic study of emamectin benzoate in cod, Gadus morhua L., held in sea water at 9 °C

The pharmacokinetic profile of the antiparasitic agent emamectin benzoate was studied in plasma after intravenous (i.v.) injection and in plasma, muscle and skin following oral (p.o.) administration to cod, Gadus morhua, held in sea water at 9 degrees C and weighing 100-200 g. Following i.v. injection, the plasma drug concentration-time profile showed two distinct phases. The plasma distribution half-life (t(1/2)alpha) was estimated as 2.5 h, the elimination half-life (t(1/2)beta) as 216 h, the total body clearance (Cl(T)) as 0.0059 L kg(-1) h(-1) and mean residence time (MRT) as 385 h. The volume of distribution at steady state, V(d(ss)), was calculated to be 1.839 L kg(-1). Following p.o. administration the peak plasma concentration (C(max)) was 15 ng mL(-1), the time to peak plasma concentration (T(max)) was 89 h and t(1/2)beta was 180 h. The highest concentration in muscle (21 ng g(-1)) was measured after 7 days and t(1/2)beta was calculated to be 247 h. For skin, a peak concentration of 28 ng g(-1) at 3 days was observed and a t(1/2)beta of 235 h was determined. The bioavailability following p.o. administration was calculated to be 38%.

Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies

A controlled drug release system based on the injectable PLGA microspheres loaded with gestodene and ethinyl estradiol was prepared and evaluated for the feasibility of monthly synchronic delivery of the two hormonal contraceptives. The scanning electron microscopy, light-scattering analyzer and gel permeation chromatography were used to study the morphology, particle size and molecular weight of the polymer microspheres, respectively. HPLC was utilized to determine the drug loading and the drug released, while a LC-MS-MS system was employed to analyze the plasma drug concentration. Result indicated that the PLGA particles obtained were spherical and appropriate in size. The formulation was stable during the test period. In vitro drug release from the microspheres for both drugs was sustained for about 30 days mostly by the diffusion mechanism. The plasma drug concentration-time profiles of the drug-loaded microspheres were relatively smooth after subcutaneous injection to rats for about 1-month, compared with that for drug suspension. In vitro and in vivo correlation was established. One of the most important facts is the synchronicity of the two contraceptives both in the release kinetics in vitro and the pharmacokinetic behaviors in vivo. Therefore, the synchronic delivery of two contraceptives is achieved for about 1 month by using the injectable PLGA-based microspheres.

Evaluation of the Contribution of the Nasal Cavity and Gastrointestinal Tract to Drug Absorption Following Nasal Application to Rats

Drugs applied to the nose in in vivo physiologic condition undergo absorption from the nasal cavity and the gastrointestinal (GI) tract because drug solution in the nasal cavity, together with mucus layer, is cleared to pharynx and then to the GI tract by coordinated beat of the cilia on nasal epithelial cells. The purpose of this study was to develop evaluate the contribution of the nasal cavity and the GI tract to drug absorption following nasal application and to clarify the relation to the transepithelial permeability of the drug (the permeability to Caco-2 monolayer, P(Caco-2)). Male Wistar rats received intravenous, nasal, and oral drug administration and drug concentration-time profiles in plasma were determined. Fractional absorption after nasal application (Fn) and oral administration (Fpo) were calculated from the area under the curve following intravenous injection (AUCiv), nasal application (AUCn), and oral administration (AUCpo) as AUCn/AUCiv and AUCpo/AUCiv, respectively. Fractional absorption from the nasal cavity (F(NC)) and the GI tract (F(GI)) following nasal application was calculated as (Fn-Fpo)/(1-Fpo) and Fpo(1-F(NC)), respectively. The shape of the curve between F(NC) and P(Caco-2) was similar with the one observed in the case of oral bioavailability except the curve shifted right. It is noteworthy that the relation between F(GI) and P(Caco-2) showed a bell-shaped curve with peak at 10(-6) cm/s of P(Caco-2). Highly permeable drug is primarily absorbed through the nasal mucosa before it is cleared to the GI tract. With the decrease in P(Caco-2), the larger amount of the drug is cleared to the GI tract and absorption from the GI tract is increased. Poorly permeable drug, on the other hand, was absorbed neither from the nasal was nor the GI tract. These findings suggest that the primary absorption site of drug after nasal application is decided by mucociliary clearance and absorption through the nasal mucosa.

The Effects of Ergoloid Mesylates and Ginkgo Biloba on the Pharmacokinetics of Ticlopidine

Ticlopidine is sometimes coadministered with ergoloid mesylates or ginkgo biloba in clinical situations. Our objective was to examine the effect of ergoloid mesylates and ginkgo biloba on ticlopidine pharmacokinetics. Ticlopidine, ergoloid mesylates, and ginkgo biloba significantly inhibited the organic anion transporting polypeptide (OATP-B)-mediated uptake of [(3)H]-estrone-3-sulfate in a concentration-dependent manner. When ergoloid mesylates was coadministered with ticlopidine, the ticlopidine area under the plasma drug concentration-time profile (AUC) from 0 to 12 hours was decreased 30% and the peak plasma drug concentration (C(max)) was decreased 29%, compared with ticlopidine administration alone. There were no significant changes in the pharmacokinetic parameters of ticlopidine when it was coadministered with ginkgo biloba. In summary, ergoloid mesylates is a more potent inhibitor of OATP-B than is ginkgo biloba, and it can reduce the oral bioavailability of drugs transported by OATP-B. Ergoloid mesylates markedly decreased the AUC and C(max) of ticlopidine, probably by inhibiting the OATP-B-mediated uptake of ticlopidine during the intestinal absorption phase. The results support a new model of intestinal drug-drug interaction.

Pharmacokinetic Model-Predicted Anticancer Drug Concentrations in Human Tumors

In an era when molecular and targeted anticancer therapeutics is a major focus and when understanding drug dynamics in tumor is critical, it seems advantageous to be able to relate drug concentrations in tumors to corresponding biological end points. To that end, a novel method, based on physiologically based hybrid pharmacokinetic models, is presented to predict human tumor drug concentrations. Such models consist of a forcing function, describing the plasma drug concentration-time profile, which is linked to a model describing drug disposition in tumors. The hybrid models are originally derived from preclinical data and then scaled to humans. Integral to the scale-up procedure is the ability to derive human forcing functions directly from clinical pharmacokinetic data. Three examples of this approach are presented based on preclinical investigations with carboplatin, topotecan, and temozolomide. Translation of these preclinical hybrid models to humans used a Monte Carlo simulation technique that accounted for intrasubject and intersubject variability. Different pharmacokinetic end points, such as the AUC tumor, were extracted from the simulated human tumor drug concentrations to show how the predicted drug concentrations might be used to select drug-dosing regimens. It is believed that this modeling strategy can be used as an aid in the drug development process by providing key insights into drug disposition in tumors and by offering a foundation to optimize drug regimen design.

A single-dose pharmacokinetic study of oxolinic acid and vetoquinol, an oxolinic acid ester, in cod, Gadus morhua L., held in sea water at 8 degrees C and in vitro antibacterial activity of oxolinic acid against Vibrio anguillarum strains isolated from diseased cod.

The pharmacokinetic properties of the antibacterial agent oxolinic acid and vetoquinol, the carbitol ester of oxolinic acid, were studied after intravenous (i.v.) and oral (p.o.) administration to 100-150 g cod, Gadus morhua L., held in sea water at 8 degrees C. Following i.v. injection, the plasma drug concentration-time profile showed two distinct phases. The distribution half-life (t1/2alpha) was estimated at 1.3 h, the elimination half-life (t1/2beta) as 84 h and the total body clearance (Cl(T)) as 0.047 L kg(-1) h(-1). The volume of distribution at steady state, Vd(ss) was calculated to be 5.5 L kg(-1), indicating good tissue penetration of oxolinic acid in cod. Following p.o. administration of oxolinic acid or vetoquinol, the peak plasma concentrations (C(max)) of oxolinic acid and the time to peak plasma concentrations (T(max) were estimated to be 1.2 and 2.5 microg mL(-1) and 24 and 12 h, respectively. The bioavailabilities of oxolinic acid following p.o. administration of oxolinic acid and vetoquinol were calculated to be 55 and 72%, respectively. The in vitro minimum inhibitory concentration (MIC) values of oxolinic acid against three strains of Vibrio anguillarum isolated from diseased cod were 0.016 microg mL(-1) (HI-610), 0.250 microg mL(-1) (HI-618) and 0.250 microg mL(-1) (HI-A21). Based on a MIC value of 0.016 microg mmL(-1) a single p.o. administration of 25 mg kg(-1) of oxolinic acid maintains plasma levels in excess of 0.064 microg mL(-1), corresponding to four times the MIC-value, for approximately 12 days. The analogous value for a single p.o. dose of 25 mg kg(-1) of oxolinic acid administered as vetoquinol was 13 days.

A New Rapidly Absorbed Paracetamol Tablet Containing Sodium Bicarbonate. II. Dissolution Studies and In Vitro/In Vivo Correlation

ABSTRACTThe objective of this study was to compare the in vitro dissolution profile of a new rapidly absorbed paracetamol tablet containing sodium bicarbonate (PS) with that of a conventional paracetamol tablet (P), and to relate these by deconvolution and mapping to in vivo release. The dissolution methods used include the standard procedure described in the USP monograph for paracetamol tablets, employing buffer at pH 5.8 or 0.05 M HCl at stirrer speeds between 10 and 50 rpm. The mapping process was developed and implemented in Microsoft Excel® worksheets that iteratively calculated the optimal values of scale and shape factors which linked in vivo time to in vitro time. The in vitro–in vivo correlation (IVIVC) was carried out simultaneously for both formulations to produce common mapping factors. The USP method, using buffer at pH 5.8, demonstrated no difference between the two products. However, using an acidic medium the rate of dissolution of P but not of PS decreased with decreasing stirrer speed. A significant correlation (r = 0.773; p<.00001) was established between in vivo release and in vitro dissolution using the profiles obtained with 0.05 M HCl and a stirrer speed of 30 rpm. The scale factor for optimal simultaneous IVIVC in the fasting state was 2.54 and the shape factor was 0.16; corresponding values for mapping in the fed state were 3.37 and 0.13 (implying a larger in vitro–in vivo time difference but reduced shape difference in the fed state). The current IVIVC explains, in part, the observed in vivo variability of the two products. The approach to mapping may also be extended to different batches of these products, to predict the impact of any changes of in vitro dissolution on in vivo release and plasma drug concentration–time profiles.

Comparative Pharmacokinetics, Tissue Distributions, and Effects on Renal Function of Novel Polymeric Formulations of Amphotericin B and Amphotericin B-Deoxycholate in Rats

The pharmacokinetic profiles of a traditional formulation of amphotericin B (Fungizone) and novel nanosphere and mixed micelle delivery systems developed for amphotericin B were compared and described. Six groups of male Wistar rats received intravenous injections of the different formulations. Plasma and tissue samples were obtained at 11 different times after dosing, with three animals used each time. The amphotericin B concentrations in plasma and tissues were analyzed by high-performance liquid chromatography. The plasma drug concentration-time profiles were best described by a two-compartment model. Models that described the observed single or double peak disposition kinetics in kidney, liver, and spleen were also developed. Parameter estimates from those models show that components of the formulation such as poloxamer 188, which is present in all new formulations, seem to play an important role in the rate of drug uptake by the tissues; in general, the levels of amphotericin B in tissues were increased after the administration of the new formulations compared with those after the administration of Fungizone. The increment in the baseline plasma creatinine level was used as an index of renal function. All formulations increased this baseline value, but the novel formulations exhibited fewer renal effects than Fungizone did. However, a direct relationship between drug exposure in the kidneys and development of renal damage could not be found.

Single dose pharmacokinetic study of flumequine after intravenous, intraperitoneal and oral administration to Atlantic halibut ( Hippoglossus hippoglossus) held in seawater at 9 °C

The pharmacokinetic properties of the antibacterial agent flumequine were studied after intravenous, intraperitoneal and oral administration to Atlantic halibut ( Hippoglossus hippoglossus) held in seawater at 9 °C and weighing 1.5-2.5 kg. Following intravenous injection the plasma drug concentration-time profile showed three distinct phases. The distribution half life ( t 1 2 α) was estimated to be 0.8 h and the terminal elimination half life ( t 1 2 γ) to be 43 h. Total body clearance (Cl T) was determined to be 0.052 1/kg h −1. The volume of distribution at steady state, V d( ss) , was estimated to be 2.3 1/kg indicating good tissue penetration of flumequine in Atlantic halibut. The peak plasma concentration ( C max) and the time to peak plasma concentrations ( T max) were estimated to be 2.7 and 6.1 μg/ml and 20 and 10 h, respectively, following oral administration of medicated feed or intraperitoneal injection. The bioavailabilities were calculated to be 31 and 69%, respectively, following oral or intraperitoneal administration. Only traces (< 10 ng/ml) of the metabolite 7-hydroxy-flumequine were found in a few of the plasma samples. Based on a minimum inhibitory concentration (MIC) of 0.0625 μg/ml for susceptible strains, a single intraperitoneal injection of 25 mg/kg of flumequine maintain plasma levels in excess of 0.25 μg/ml corresponding to 4 times the MIC-value, for approximately 10 d. The corresponding value for a single oral dose of 25 mg/kg of flumequine given as medicated feed, was 5 d.

Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium-99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration-time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/- 0.4 h, mean +/- s.d.), and the time to arrival in the colon (3.8 +/- 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/- 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration-time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.

Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine.

The hydrochloride, sulphate and ethylcarbonate salts of quinine were given in single oral doses (600 mg base equivalent) to nine healthy male subjects according to a cross-over design. No statistically significant differences were noted in the plasma drug concentration-time profiles although inter- and intra-subject variation in AUC, Cmax and tmax values was appreciable. The ethylcarbonate salt may be preferred for use in paediatric patients because of its neutral taste.

Isosorbide Dinitrate Plasma Concentrations and Bioavailability in Human Subjects after Administration of Standard Oral and Sublingual Formulations

The bioavailability of isosorbide dinitrate from formulations containing 5,10, and 20 mg in tablets and 10 mg in solution for oral use and 5 mg in tablets for sublingual use, has been compared. When adjusted for dose, the peak mean plasma drug concentrations after oral administration were similar (e.g., 9.2 ng/mL after a 10-mg tablet) and about one-half that obtained after sublingual administration. Drug concentrations declined monoexponentially with mean half-lives ranging from 25–36 min. The relative bioavailability of isosorbide dinitrate from the oral formulations was not significantly different (p > 0.05) over the dose range studied, whereas the relative bioavailability after sublingual administration was about twice as great (p < 0.01) as that after oral administration. The plasma drug concentration-time profile after administering the 5-mg sublingual tablet was similar to that obtained after administering orally a solution containing 10 mg, indicating that the latter should be as clinically effective as the former.